Compositions and methods for enhancing nitric oxide delivery

Abstract

The present invention is directed to compounds, combinations, compositions and methods for enhancing nitric oxide (NO) delivery to target sites, and in particular to muscle, both normal and dystrophic. Enhanced NO delivery according to the present invention may be achieved by using a combination of a muscle relaxant and an NO donor compound, or by using a compound of the invention: formula (I) wherein R 1 is H, halo, C 1-6 alkoxy or C 1-6 alkyl; R 2 is H, NO 2 or C(O)NH 2 ; R 3 is H, NO 2 or C(O)NH 2 ; and at least one of R 2 and R 3 is NO 2 ; or a pharmaceutically acceptable salt of the compound.

1. A pharmaceutical composition comprising a combination of methocarbamol and 1,2-di-O-nitro-3(o-methoxyphenoxy)-propanediol; and a pharmaceutically acceptable diluent or carrier. 
     
     
       2. A pharmaceutical composition of  claim 1  for: promoting muscle cell proliferation or repair in normal muscle in need thereof, regulating satellite cell proliferation in dystrophic muscle or treating muscular dystrophy. 
     
     
       3. The pharmaceutical composition of  claim 1  suitable for transdermal delivery. 
     
     
       4. The pharmaceutical composition of  claim 1 , which is a parenteral formulation, an oral dosage form, an intraperitoneal formulation, an intra-uterine formulation, an intrapleural formulation, a suppository for use vaginally or rectally, an inhalant formulation, a controlled-release implant or a patch. 
     
     
       5. The compound of formula: 
       
         
           
           
               
               
           
         
       
     
     
       6. A commercial package comprising the pharmaceutical composition of  claim 1  and instructions for the use thereof for promoting muscle cell proliferation repair in normal muscle in need thereof, for regulating satellite cell proliferation in dystrophic muscle or for treating muscular dystrophy. 
     
     
       7. A method for promoting formation of muscle tissue or repair of damaged muscle tissue, the method comprising administering an effective amount of a pharmaceutical composition of  claim 1  to a subject in need of formation of muscle tissue or repair of damaged muscle tissue. 
     
     
       8. A method for facilitating transdermal delivery of 1,2-di-O-nitro-3(o-methoxyphenoxy)-propanediol to a target site in a subject, the method comprising applying methocarbamol to a skin region on the site along with application of 1,2-di-O-nitro-3(o-methoxyphenoxy)-propanediol. 
     
     
       9. The method of  claim 7 , wherein the subject suffers from a skeletal muscle injury or muscular dystrophy. 
     
     
       10. The method of  claim 7 , wherein the subject is a human or a non-human animal. 
     
     
       11. A method for making the compound of formula: 
       
         
           
           
               
               
           
         
         comprising dinitrosylating guaifenesin. 
       
     
     
       12. The method of  claim 8 , wherein the subject suffers from a skeletal muscle injury or muscular dystrophy. 
     
     
       13. The method of  claim 8 , wherein the subject is a human or a non-human animal.